Liver performs over 5 hundred vital functions including detoxification of toxic substances, synthesis and secretion of bile acids or bile pigments, synthesis and metabolism of plasma protein, and metabolism of glucose and lipid. Therefore, unlike heart and kidney, it is not possible to replace such liver functions by a simple system comprising a pump or a dialysis membrane (see Mito M., Artificial Organs, 10, 214-218, 1986). Although recent liver transplantation patients have shown a high survival rate, according to the Scientific Registry of United Network for Organ Sharing, only about 10% of the registering patients can receive liver transplantation in the U.S. because of the extreme shortage of organ donors, and the number of patients who expired while waiting for a liver transplant has been rapidly increasing.
Thus, there is a dire need to develop a viable liver support device such as an artificial liver, which can be efficiently and conveniently applied to keep a patient alive and minimize the sequelae of liver failure including neurological damage during the recovery of liver functions or the regeneration of the patient's native liver, and during the waiting period for receiving liver transplantation.
Therefore, there have been conducted a number of studies on a bioartificial liver system using animal hepatocytes, which can perform various biological functions of hepatocytes (see Kamlot A. et al., Biotechnol Bioeng., 50, 382-391, 1996). Such bioartificial liver comprising hepatocytes can significantly alleviate the symptoms of hepatic failure and extend the survival period, by performing the steps of separating plasma from the blood stream of a patient, treating the plasma in a bioreactor tightly packed with hepatocytes, and returning the treated plasma to the patient. Accordingly, a viable bioartificial liver must be able to cultivate hepatocytes while maintaining their functions intact and also to have a high throughput capacity.
A hollow-fiber reactor used in kidney dialysis has been applied to a bioartificial liver system due to its well-developed technology. However, this type of reactor can accommodate only a small amount of hepatocytes, which limits the reactor's throughput capacity (see Demetriou A. A. et al., Ann. Surg., 239, 660-667, 2004).
In order to solve the above-mentioned problem, there has been reported a gel-bead type or capsule type bioreactor in which hepatocytes are packed within gel beads or capsules (see David B. et. al., Int. J. Artif. Organs., 27(4), 284-293, 2004; and Xu Q. et al., Ann. Clin. Lab. Sci., 34(1), 87-93, 2004). However, this type of fixed-bed bioreactor has several problems such as damage of fragile gel beads caused by the applied pressure for circulation and depletion of oxygen and nutrients caused by channeling, which leads to necrosis of hepatocytes.
Therefore, most of recently developed gel bead type bioreactors have been in the form of a fluidized-bed in which the gel beads move freely with the flow of the fluid in the reactor (see David B. et al., Int. J. Artif. Organs, 27(4), 284-293, 2004; M. Desille et al., Crit. Care Med., 30(3), 658-663, 2002; Y. J. Hwang et al., Transpl. Proc., 32, 2349-2351, 2000; and C. Legallais et al., Artificial Organs, 24(7), 519-525, 2000).
However, such a fluidized-bed reactor is disadvantageous in that it has a relatively larger reactor volume as compared with a fixed-bed reactor and the plasma throughput rate is unacceptably low (see M. Desille et al., Crit. Care Med., 30(3), 658-663, 2002; and Y. J. Hwang et al., Transpl. Proc., 32, 2349-2351, 2000, E. Dore et al., Therapeutic Apheresis, 3(3), 264-267, 1999). In this regard, it has been reported that considering the oxygen consumption rate of hepatocytes, a fluidized reactor having 2×1010 hepatocytes needs a plasma flow rate of at least 150 ml/min in order to supply sufficient oxygen (see Florence J. et al., Biotechnol. Bioeng., 50, 404-415, 1996).
In order to overcome aforementioned problems, a gel bead type-packed upflow fixed-bed reactor has been proposed (see T. M. Rahman et al., Artificial Organs, 28(5), 476-482, 2004), but it has the problem that the throughput rate is too small for treating a hepatic failure patient.
Further, in case of a conventional downflow reactor (see F. Meuwly et al., J. Biotechnology, 122, 122-129, 2006), no damage of the packing material occurs when a disk type fibrous packing material having high strength and porosity is used as a cell holder, but the performance of this reactor may deteriorate, or efflux of the circulating fluid may occur due to the high pressure generated by the use of a tube pump.